Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma

Abstract

BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes. Typically, under BRAFi pressure, death of BRAFi-sensitive cells leads to an enrichment of a small subpopulation of AhR-activated and BRAFi-persister cells, responsible for relapse. Also, differentiated and BRAFi-sensitive cells can be redirected towards an AhR-dependent resistant program using AhR agonists. We thus identify Resveratrol, a clinically compatible AhR-antagonist that abrogates deleterious AhR sustained-activation. Combined with BRAFi, Resveratrol reduces the number of BRAFi-resistant cells and delays tumor growth. We thus propose AhR-impairment as a strategy to overcome melanoma resistance.

Clinical outcomes of BRAF plus MEK inhibition in melanoma: A meta‐analysis and systematic review

“…Mechanisms of resistance were fasten on MAPK (mitogen‐activated protein kinase) pathway reactivation, gene expression change including acquired overexpression of upstream NRSA and MEK mutations, amplification or alternate splicing of mutant BRAF, reactivation and autophagy of ERK (extracellular regulated protein kinases), COT and MLKs overexpression . Besides, tumor microenvironment change such as microRNA and aryl hydrocarbon receptor (AhR) transcription factor has been found in BRAF resistance . Immune microenvironment change such as increasing PD1+ melanoma cells was also related to tumor recurrence .…”

“…26 Besides, tumor microenvironment change such as microRNA and aryl hydrocarbon receptor (AhR) transcription factor has been found in BRAF resistance. 27,28 Immune microenvironment change such as increasing PD1+ melanoma cells was also related to tumor recurrence. 29 These findings suggested that the occurrence of acquired resistance could be prevented or delayed in combination therapy, which included downstream target inhibition and BRAF inhibition.…”

Gain-of-function CRISPR screens identify tumor-promoting genes conferring melanoma cell plasticity and therapy-resistance

“…We selected the 501Mel cell line since i) these cells display a melanocytic differentiation state as the majority of diagnosticated melanoma, ii) they harbor the BRAF(V600E) mutation as ~50% of cutaneous melanoma, iii) they are highly sensitive to BRAFi with an IC50 value of 0.45 µM to vemurafenib [PLX4032] 18,28 and importantly iv) they are unable to generate tumor in immunodeficient mice 29 . This latter characteristic may allow to identify tumor-promoting genes.…”

“…Such alterations may also occur de novo, during treatment 12 . In addition, there is increased evidence that nongenetic reprogramming may confer drug tolerant and/or resistant phenotypes to melanoma cells 6,[16][17][18][19][20] . Earlier works demonstrated that phenotype switching from a proliferative to an invasive/mesenchymal-like state is also likely to contribute to therapy resistance [21][22][23][24][25] .…”

Antimigraine Drug Avitriptan Is a Ligand and Agonist of Human Aryl Hydrocarbon Receptor that Induces CYP1A1 in Hepatic and Intestinal Cells

“…An anti-leprosy Food and Drug Administration (FDA)-approved drug and AhR antagonist clofazimine suppressed multiple myeloma in transgenic mice [8]. Targeting of AhR with antagonists was suggested as a strategy for delaying the relapse during the treatment of melanoma with vemurafenib [9] or for inhibiting constitutive AhR activity in prostate cancer [10]. The use of AhR ligands is not limited to anti-cancer therapy but given the roles of AhR in the intestines and skin, targeting the AhR is challenging also in the treatment of inflammatory bowel disease (IBD) or skin pathologies.…”